Tackling the Bioavailability Bottleneck in Oral Drug Development
By Richard Johnson, Chief Scientific Officer, Upperton
Despite continued advances in medicinal chemistry and target biology, failure rates in clinical drug development remain stubbornly high. A significant proportion of late stage attrition can be traced back not to a lack of efficacy, but to poor ADME characteristics, most notably insufficient oral bioavailability. As the pharmaceutical industry increasingly focuses on complex, lipophilic small molecules, this long standing challenge has become even more pronounced.
Oral solid dosage forms remain the preferred route of administration for most small molecule drugs, offering well established regulatory pathways, patient convenience, and scalable manufacturing. However, many promising candidates struggle to achieve adequate systemic exposure when delivered orally. Poor aqueous solubility, slow dissolution, and formulation instability frequently prevent sufficient drug absorption, particularly for compounds falling into Biopharmaceutics Classification System (BCS) Classes II and IV. In these cases, bioavailability is driven less by intrinsic permeability and more by formulation performance.
A key problem is timing. Solubility and absorption risks are often identified too late in development, after substantial investment in synthesis, toxicology, and early clinical work. Reformulating at this stage is costly, disruptive, and can delay or derail programmes entirely. The industry’s increasing awareness of developability has helped, but many development teams still lack structured, early stage tools to predict and mitigate bioavailability risk before it becomes a bottleneck.
Fundamentally, oral bioavailability depends on a series of sequential steps: a drug must dissolve in gastrointestinal fluids, permeate the intestinal membrane, and survive first pass metabolism. While permeability and metabolism are often fixed properties of the molecule, solubility and dissolution behaviour can frequently be improved through formulation. Enabling technologies such as amorphous solid dispersions, lipid based systems, micronisation, and particle engineering are well established, but selecting the right approach for a given compound is not always straightforward.
This is where early, data driven formulation screening can deliver significant value. Rather than committing prematurely to a single formulation concept, comparative evaluation across multiple enabling strategies allows teams to identify which approaches genuinely improve in vivo exposure - and which do not. Importantly, this needs to be done using minimal active pharmaceutical ingredient (API) and within timelines compatible with preclinical development.
The UpperSolv™ platform has been designed specifically to address this need. Acting as an early stage formulation screening and decision making tool, it combines formulation development with integrated in vitro and in vivo assessment to rapidly identify the most promising oral formulation strategies for poorly soluble compounds. Using as little as 5 grams of API, UpperSolv™ can screen up to six formulation approaches in parallel, delivering comparative pharmacokinetic data within approximately six to eight weeks.
The workflow begins with solubility and compatibility screening across a wide range of solvents, excipients, and vehicles. Based on these data, prototype formulations are prepared using technologies such as spray dried dispersions, lipid based systems, or micronised powders. These prototypes undergo biorelevant dissolution testing and stability assessment before progressing into small animal pharmacokinetic studies. This integrated approach ensures that formulation decisions are driven by exposure data rather than assumptions.
Critically, the outcome is not just data, but clarity. Sponsors receive a ranked comparison of formulation strategies, supported by physicochemical, in vitro, and in vivo evidence, along with a clear recommendation for the most suitable path into toxicology, first in human studies, or clinical manufacture. By identifying and addressing bioavailability risk early, development teams can avoid costly reformulation cycles, accelerate timelines, and enter the clinic with greater confidence.
As oral drug candidates continue to push the boundaries of solubility and complexity, early formulation strategy is no longer a “nice to have” - it is a prerequisite for success. Structured platforms like UpperSolv™ demonstrate how integrating formulation science and biopharmaceutics at the outset can de risk development and help transform promising molecules into viable oral medicines.
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